1. Field of the Invention
The present invention relates generally to the fields of cell biology, developmental biology and medicine. More particularly, it concerns methods and compositions relating to the stimulation of insulin production and the treatment of diabetes.
2. Description of Related Art
Nearly one-third of the adult population of the United States is at risk for type 2 diabetes because of abnormal glucose tolerance or abnormally high fasting glucose (Genuth et al., 2003). Type 2 diabetes is increasing at an alarming rate and is now found not only in adults but also in chronically overweight children. Pancreatic β cells play a unique role in glucose homeostasis by secreting insulin when the concentrations of glucose and other nutrients in the circulation rise (Newgard and McGarry, 1995). Insulin facilitates proper nutrient utilization and storage by most tissues. Beta cells are vulnerable to persistent nutrient excess from secretory stress. During the development of type 2 diabetes, pancreatic beta cells become progressively unable to produce and secrete sufficient insulin to prevent hyperglycemia (Genuth et al., 2003; Muoio and Newgard, 2008; Rutter and Parton, 2008). Identifying strategies to maintain euglycemia is essential to limit diabetes and its destructive consequences (Halban et al., 2010; Borowiak and Melton, 2009).
Nutrients regulate insulin production at several steps in the biosynthetic pathway in addition to its secretion, including cleavage of the preprohormone, translation, and transcription (Redmon et al., 1994; Xu et al., 1998; Wicksteed et al., 2007; Steiner et al., 2009; Goodge and Hutton, 2000). The immediate events to replenish secreted insulin involve translation of pre-existing mRNA and hormone processing. On a longer time scale, new insulin gene transcription maintains the pool of mRNA for translation on demand.
Insulin gene transcription is regulated by the cooperation of a group of glucose-sensitive transcription factors expressed in a tissue-restricted manner (Ohneda et al., 2000; Aramata et al., 2005). Among the most important of these, the basic-loop-helix (bHLH) factor BETA2 (also known as NeuroD1), the homeodomain factor PDX-1, and the basic leucine zipper factor MafA have been shown to activate the insulin gene promoter synergistically and are essential for glucose-stimulated insulin gene transcription. Mutations in PDX-1 and BETA2 have been linked to maturity onset diabetes of the young (MODY) and are classified as MODY4 and MODY6 genes, respectively (Habener and Stoffers, 1998; Vaxillaire and Froguel, 2008).
BETA2 is required during neuronal development for the differentiation of neuronal progenitor cells in the central and peripheral nervous system (Kageyama et al., 1997; Chae et al., 2004). BETA2 also has an essential role in the development of neuroendocrine cells in other organs including lung, intestine, and pancreas. In the adult, the main function of BETA2 is in pancreatic β cells, although it is also required for continued neurogenesis in the hippocampal CA1 region of the brain. The neurogenin (Ngn) family of bHLH proteins are direct transcriptional regulators of BETA2 during neuronal and pancreatic development (Huang et al., 2000; Sommer et al., 1996). While Ngn1 and 2 act exclusively in neuronal lineages, Ngn3 is the family member that induces BETA2 expression in pancreatic β cells. Several studies have reported that expression of one or more of these factors helps to promote differentiation of pancreatic endocrine cells from various stem cell populations (Borowiak and Melton, 2009; Gasa et al., 2004). However, the precise role played in pancreatic development is not understood.